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. 2007 Aug 23;50(17):3973-5.
doi: 10.1021/jm070638m. Epub 2007 Jul 21.

Discovery of 1,4-dihydroxy-2-naphthoate [corrected] prenyltransferase inhibitors: new drug leads for multidrug-resistant gram-positive pathogens

Michio Kurosu  1 , Prabagaran Narayanasamy, Kallolmay Biswas, Rakesh Dhiman, Dean C Crick
Affiliations

Discovery of 1,4-dihydroxy-2-naphthoate [corrected] prenyltransferase inhibitors: new drug leads for multidrug-resistant gram-positive pathogens

Michio Kurosu et al. J Med Chem. .

Erratum in

  • J Med Chem. 2007 Oct 4;50(20):5048

Abstract

Since utilization of menaquinone in the electron transport system is a characteristic of Gram-positive organisms, the 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) inhibitors 1a and 2a act as selective antibacterial agents against organisms such as methicillin-resistant Stapylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE), and Mycobacterium spp. Growth of drug-resistant Gram-positive organisms was sensitive to the MenA inhibitors, indicating that menaquinone synthesis is a valid new drug target in Gram-positive organisms.

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Figures

Figure 1
Figure 1
Schematic bacterial electron transport chain and menaquinone biosynthesis.
Scheme 1
Scheme 1
Generation of a Library of Molecules in Solution,a a Reagents and conditions: (a) AlCl3, PhNO2 (75-90%); (b) (i) 48% HBr, AcOH (90%); (ii) 1,5-dibromopentane or 1,6-dibromohexane or 1,7-dibromoheptane or 1,8-dibromooctane, K2CO3, DMF (for 1) (80-95%); 1,4-dibromobutane, K2CO3, DMF; 1,3-propanediol, NaH, DMF; CBr4, PPh3, CH2Cl2 (for 2) (65%); 1,4-dibromobutene, K2CO3, DMF; 1,3-propanediol, NaH, DMF; CBr4, PPh3, CH2Cl2 (for 3) (65%); 1,4-dibromobutyne, K2CO3, DMF; 1,3-propanediol, NaH, DMF; CBr4, PPh3, zCH2Cl2 (for 4) (65%); (iii) R5 (primary or secondary amines or hydrazines), NaHCO3, DMF (50-98%); (iv) TFA, CH2Cl2 (for Boc-protected R5) (100%).
See this image and copyright information in PMC

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    1. The peptide sequences of the menA and ubiA gene products were only 21% identity and 35% similarity. See the following:Suvana KD, Stevenson R, Meganathan R, Hudspeth MES. Menaquinone (vitamin K2) biosynthesis: localization and characterization of the menA Gene from Escherichia coli. J. Bacteriol. 1998;180:2782–2787.

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